Spinal cord injury (SCI) is a serious medical problem that causes loss of sensory, motor and autonomic function due to the damage of central nerve cells. There are no fully restorative therapies for SCI so far, but there is one FDA approved agent methylprednisolone (MP) that is being used clinically for the improvement of function after acute injury because of their high lipid peroxidation inhibition and anti-inflammatory potency. However, the use of this drug remains controversial as the modest protective functions on nerve cells are overshadowed by the unfavorable side effects to the rest of the body. To increase efficacy and reduce their side effects, we have designed and synthesized a nanoparticles- conjugated MP (Nano-MP), which is composed of MP and a carrier (N2-hydroxypropyl methacrylamide). Our exciting preliminary data demonstrated that the Nano-MP, by a single administration, is able to be preferentially delivered to the site of the injured spinal cord in a rodent model of SCI, where the drug is sequestered and retained mainly by infiltrating inflammatory cells (extrapolated from the action of the parent MP molecule) for several days. Compared to conventional intravenous delivery of the MP molecule, the single dose of the Nano- MP administration significantly inhibited oxidative stress in the injured spinal cord. Additionally, we established a similar nanoparticle delivery of dexamethasone as an anti-inflammatory agent with increased efficacy and reduced side effects in adjuvant-induced arthritis and lupus nephritis. Based on this evidence, we hypothesize that the targeted MP delivery to the injury site has similar or superior therapeutic efficacy (e.g., because of greater delivery efficiency, this approach will be associated with reduced lipid peroxidation, inflammation and neural damage) in the treatment of acute SCI while reducing side effects (e.g., those adversely affecting muscle, bone), compared to conventional intravenous delivery of the parent MP molecule. In this R21 project, we propose to a series of preclinical experiments to test our hypotheses. We will first determine the potential therapeutic efficacy of Nano-MP on lipid peroxidation, oxidative stress, inflammation, neural damage and wound-healing after acute SCI (Aim 1). We will further evaluate if Nano-MP administration, compared to that of free MP, results in a reduction in adverse effects on skeletal muscle and bone after acute SCI (Aim 2). The successful completion of the projects of this kind is expected to provide an evidence-based rationale to further evaluate the effects of Nano-MP on functional recovery after acute SCI, and to strongly support early clinical studies to test the efficacy of this innovative treatment. If it proven to efficacious in further studies, administration of nanotechnology-enabled MP holds the potential to be a practical and truly exciting major advance to preserve function in individuals after acute SCI. The completion of this line of research will lead to a safe, convenient, effective, and affordable targeted-therapy to provide neuroprotection and to improve functional recovery for persons with acute SCI.